Poxvirus-encoded TNF decoy receptors inhibit the biological activity of transmembrane TNF

© 2015 The Authors. Poxviruses encode up to four different soluble TNF receptors, named cytokine response modifier B (CrmB), CrmC, CrmD and CrmE. These proteins mimic the extracellular domain of the cellular TNF receptors to bind and inhibit the activity of TNF and, in some cases, other TNF superfamily ligands. Most of these ligands are released after the enzymic cleavage of a membrane precursor. However, transmembrane TNF (tmTNF) is not only a precursor of soluble TNF but also exerts specific pro-inflammatory and immunological activities. Here, we report that viral TNF receptors bound and inhibited tmTNF and describe some interesting differences in their activity against the soluble cytokine. Thus, CrmE, which does not inhibit mouse soluble TNF, could block murine tmTNF-induced cytotoxicity. We propose that this anti-tmTNF effect should be taken into consideration when assessing the role of viral TNF decoy receptors in the pathogenesis of poxvirus.Ministry of Economy and Competitiveness Grants SAF2009-07857 and SAF2012-38957.S. M. P. was recipient of a JAE PhD Studentship from Consejo Superior de Investigaciones Científicas and a studentship from Fundación Severo OchoaPeer Reviewe

Comparative biochemical and functional analysis of viral and human secreted tumor necrosis factor (TNF) decoy receptors

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. The blockade of tumor necrosis factor (TNF) by etanercept, a soluble version of the human TNF receptor 2 (hTNFR2), is a well established strategy to inhibit adverse TNF-mediated inflammatory responses in the clinic. A similar strategy is employed by poxviruses, encoding four viral TNF decoy receptor homologues (vTNFRs) named cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. These vTNFRs are differentially expressed by poxviral species, suggesting distinct immunomodulatory properties. Whereas the human variola virus and mouse ectromelia virus encode one vTNFR, the broad host range cowpox virus encodes all vTNFRs. We report the first comprehensive study of the functional and binding properties of these four vTNFRs, providing an explanation for their expression profile among different poxviruses. In addition, the vTNFRs activities were compared with the hTNFR2 used in the clinic. Interestingly, CrmB from variola virus, the causative agent of smallpox, is the most potent TNFR of those tested here including hTNFR2. Furthermore, we demonstrate a new immunomodulatory activity of vTNFRs, showing that CrmB and CrmD also inhibit the activity of lymphotoxin β. Similarly, we report for the first time that the hTNFR2 blocks the biological activity of lymphotoxin β. The characterization of vTNFRs optimized during virus-host evolution to modulate the host immune response provides relevant information about their potential role in pathogenesis and may be used to improve anti-inflammatory therapies based on soluble decoy TNFRs.Ministry of Economy and Competitiveness Grants SAF2009-07857 and SAF2012-38957Peer Reviewe

Características moleculares y funcionales de los receptores solubles del TNF con capacidad anti-quimioquinas de poxvirus

Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 20-04-201

Insights into ligand binding by a viral tumor necrosis factor (TNF) decoy receptor yield a selective soluble human type 2 TNF receptor

Etanercept is a soluble form of the tumor necrosis factor receptor 2 (TNFR2) that inhibits pathological tumor necrosis factor (TNF) responses in rheumatoid arthritis and other inflammatory diseases. However, besides TNF, etanercept also blocks lymphotoxin- (LT), which has no clear therapeutic value and might aggravate some of the adverse effects associated with etanercept. Poxviruses encode soluble TNFR2 homologs, termed viral TNF decoy receptors (vTNFRs), that display unique specificity properties. For instance, cytokine response modifier D (CrmD) inhibits mouse and human TNF and mouse LT, but it is inactive against human LT. Here, we analyzed the molecular basis of these immunomodulatory activities in the ectromelia virus– encoded CrmD. We found that the overall molecular mechanism to bind TNF and LT from mouse and human origin is fairly conserved in CrmD and dominated by a groove under its 50s loop. However, other ligand-specific binding determinants optimize CrmD for the inhibition of mouse ligands, especially mouse TNF. Moreover, we show that the inability of CrmD to inhibit human LT is caused by a Glu-Phe-Glu motif in its 90s loop. Importantly, transfer of this motif to etanercept diminished its anti-LT activity in >60-fold while weakening its TNF-inhibitory capacity in 3-fold. This new etanercept variant could potentially be used in the clinic as a safer alternative to conventional etanercept. This work is the most detailed study of the vTNFR–ligand interactions to date and illustrates that a better knowledge of vTNFRs can provide valuable information to improve current anti-TNF therapies.Spanish Ministry of Economy and Competitiveness Grants SAF2012-38957 and SAF2015-67485-R and the European Union (European Regional Development Fun

Poxviral CrmD is an essential virulence factor

The role of cytokines and chemokines in anti-viral defense has been demonstrated, but their relative contribution to protective anti-viral responses in vivo is not fully understood. Cytokine response modifier D (CrmD) is a secreted receptor for TNF and lymphotoxin containing the smallpox virus-encoded chemokine receptor (SECRET) domain and is expressed by ectromelia virus, the causative agent of the smallpox-like disease mousepox. Here we show that CrmD is an essential virulence factor that controls natural killer cell activation and allows progression of fatal mousepox, and demonstrates that both SECRET and TNF binding domains are required for full CrmD activity. Vaccination with recombinant CrmD protects animals from lethal mousepox. These results indicate that a specific set of chemokines enhance the inflammatory and protective anti-viral responses mediated by TNF and lymphotoxin, and illustrate how viruses optimize anti-TNF strategies with addition of a chemokine binding domain as soluble decoy receptors.This work was funded by Grants from the Spanish Ministry of Economy and Competitiviness and European Union (European Regional Development’s Funds, FEDER) (grant SAF2015-67485-R), and the Wellcome Trust (grant 051087/Z97/Z). M. B. R.-A. and A. Alejo were recipients of a Ramón y Cajal Contract from the Spanish Ministry of Science and Innovation

Yanapanakuna: economía comunitaria en tiempos de crisis sanitaria y política en Bolivia

El artículo examinó de las instituciones de solidaridad y reciprocidad reconocidas como parte de la economía comunitaria en comunidades de origen andino de cinco ecorregiones de Bolivia durante la crisis que combinó la emergencia sanitaria de la COVID-19, las medidas de represión del gobierno transitorio y la incertidumbre sobre la convocatoria a elecciones generales de 2020. Se optó por una aproximación mixta que combina el análisis estadístico y el análisis comparativo; se emplearon las bases de datos de dos encuestas de hogares realizadas por la Universidad Indígena Boliviana Quechua Casimiro Bolivia Huanca correspondientes a 2019 y 2020 y en 2021 se desarrolló un cuestionario con comunarios que estudian en la universidad. Los efectos de la pandemia no se separan de los problemas políticos; la crisis debe considerarse como un fenómeno complejo múltiple. Las comunidades respondieron al mismo tiempo a la amenaza de los contagios y a las medidas de restricción y represión gubernamental. En las regiones del Trópico cocalero y en los valles interandinos acudieron a las prácticas de ayuda mutua, solidaridad y reciprocidad en mayor medida que antes de la pandemia; en la región andina no hubo variaciones. Las comunidades tropicales ampliaron la práctica del trueque y llevaron cargamentos de productos locales a zonas rurales y urbanas de seis departamentos del país, desafiando la cuarentena y la persecución gubernamental, para cambiarlos por otros productos y por plantas medicinales. Estas acciones expresan no solo la vitalidad de las prácticas colectivas sino también la innovación durante la crisis

Chemokines cooperate with TNF to provide protective anti-viral immunity and to enhance inflammation

The role of cytokines and chemokines in anti-viral defense has been demonstrated, but their relative contribution to protective anti-viral responses in vivo is not fully understood. Cytokine response modifier D (CrmD) is a secreted receptor for TNF and lymphotoxin containing the smallpox virus-encoded chemokine receptor (SECRET) domain and is expressed by ectromelia virus, the causative agent of the smallpox-like disease mousepox. Here we show that CrmD is an essential virulence factor that controls natural killer cell activation and allows progression of fatal mousepox, and demonstrate that both SECRET and TNF binding domains are required for full CrmD activity. Vaccination with recombinant CrmD protects animals from lethal mousepox. These results indicate that a specific set of chemokines enhance the inflammatory and protective anti-viral responses mediated by TNF and lymphotoxin, and illustrate how viruses optimize anti-TNF strategies with the addition of a chemokine binding domain as soluble decoy receptors.We thank Javier Salguero for help with animal experimentation and immunohistochemistry, Rocío Martín and Carolina Sánchez for technical assistance and Daniel Rubio for discussions on the project. This work was funded by Grants from the Spanish Ministry of Economy and Competitiviness and European Union (European Regional Development’s Funds, FEDER) (grant SAF2015-67485-R), and the Wellcome Trust (grant 051087/Z97/Z). M.B.R.-A. and A. Alejo were recipients of a Ramón y Cajal Contract from the Spanish Ministry of Science and Innovation

IL-27 induces an IFN-like signature in murine macrophages which in turn modulate colonic epithelium

Mucosal delivery of IL-27 has been shown to have a therapeutic benefit in murine models of inflammatory bowel disease (IBD). The IL-27 effect was associated with phosphorylated STAT1 (pSTAT1), a product of IL27 receptor signaling, in bowel tissue. To determine whether IL-27 acted directly on colonic epithelium, murine colonoids and primary intact colonic crypts were shown to be unresponsive to IL-27 in vitro and to lack detectable IL-27 receptors. On the other hand, macrophages, which are present in inflamed colon tissue, were responsive to IL-27 in vitro. IL-27 induced pSTAT1 in macrophages, the transcriptome indicated an IFN-like signature, and supernatants induced pSTAT1 in colonoids. IL-27 induced anti-viral activity in macrophages and MHC Class II induction. We conclude that the effects of mucosal delivery of IL-27 in murine IBD are in part based on the known effects of IL27 inducing immunosuppression of T cells mediated by IL-10. We also conclude that IL-27 has potent effects on macrophages in inflamed colon tissue, generating mediators that in turn act on colonic epithelium

Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a life-saving procedure used for the treatment of selected hematological malignancies, inborn errors of metabolism, and bone marrow failures. The role of neutrophils in alloHSCT has been traditionally evaluated only in the context of their ability to act as a first line of defense against infection. However, recent evidence has highlighted neutrophils as key effectors of innate and adaptive immune responses through a wide array of newly discovered functions. Accordingly, neutrophils are emerging as highly versatile cells that are able to acquire different, often opposite, functional capacities depending on the microenvironment and their differentiation status. Herein, we review the current knowledge on the multiple functions that neutrophils exhibit through the different stages of alloHSCT, from the hematopoietic stem cell (HSC) mobilization in the donor to the immunological reconstitution that occurs in the recipient following HSC infusion. We also discuss the influence exerted on neutrophils by the immunosuppressive drugs delivered in the course of alloHSCT as part of graft-versus-host disease (GVHD) prophylaxis. Finally, the potential involvement of neutrophils in alloHSCT-related complications, such as transplant-associated thrombotic microangiopathy (TA-TMA), acute and chronic GVHD, and cytomegalovirus (CMV) reactivation, is also discussed. Based on the data reviewed herein, the role played by neutrophils in alloHSCT is far greater than a simple antimicrobial role. However, much remains to be investigated in terms of the potential functions that neutrophils might exert during a highly complex procedure such as alloHSCT

Unión a glicosaminoglicanos de proteínas con dominio SECRET codificadas por poxvirus

La presente invención hace referencia al uso de un dominio SECRET de proteínas con dominio SECRET codificadas por poxvírus (CrmB, CrmD, SCP-1, SCP-2 y SCP-3), sus homólogos funcionales, derivados o fragmentos, capaces de unirse a glicosaminoglicanos (GAGs) para la fabricación de un medicamento para el tratamiento de enfermedades autoinmunes o inflamatorias, caracterizado porque dicho dominio SECRET se selecciona de entre una de las siguientes secuencias: SEQ ID N° 6, SEQ ID N° 8, SEQ ID N° 14, SEQ ID N° 16, SEQ ID N° 18, SEQ ID N° 20, SEQ ID N° 22, SEQ ID N° 24, SEQ ID N° 26, y SEQ ID N° 28. La presente invención también protege el uso de dicho medicamento para incrementar la estabilidad y/o las propiedades inmunomoduladoras de una proteína seleccionada entre: CrmB, CrmD, SCP-1, SCP-2 y SCP-3, así como su fusión a un vTNFR, o a un anticuerpo humanizado anti-TNF.Peer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic